AIDS dementia is a common manifestation of HIV infection. SIV infection of rhesus macaques provides an excellent model by which to examine the mechanisms of HIV-induced CNS disease. Our hypothesis is that the development of CNS disease requires the presence of a macrophage-tropic neurotropic strain of the virus, that blood-brain barrier dysfunction occurs during infection leading to amplification of virus load in the CNS and to neurological dysfunction, and that CNS disease can be correlated with virus replication in the brain. The first aim of this proposal is to identify host factors which are important in the development of SIV encephalitis. Rhesus macaques will be inoculated with macrophage-tropic, neurotropic strains of SIV and euthanized at various stages of infection to examine the cellular and viral processes that lead to disease. The integrity of the BBB will be studied using a battery of tests including i) evaluation of the physical component of the BBB by measuring leakage, ii) investigation of biochemical factors involved in the maintenance of BBB function and iii) measurement of neovascularization in areas of inflammation. Tissue sections and samples of bone marrow, blood and CSF from infected animals will be examined for increased expression of cellular adhesion molecules (in conjunction with Project 2) and the cytokines that induce them. The second aim is to determine the role of virus load and cell tropism in disease by quantitating virus in bone marrow, blood, CSF and brain throughout the course of infection, by determining the cell tropism of the isolated viruses, and by relating these findings to alterations in viral sequence (in conjunction with Project 3). The third aim is to characterize the cytokine-associated induction of cell adhesion molecules in cultured brain endothelial cells and to investigate the interactions of these cells with infected microglia and lymphocytes. The fourth aim is to determine whether the onset of severity of SIV encephalitis is altered by intraventricular infusion of cell adhesion molecule-inducing, pro-inflammatory cytokines. The overall objective of the study is to characterize the host and viral factors which contribute to the development and progression of lentivirus-induced CNS disease with the view of providing a basis for rational interventional and therapeutic strategies.